212 Section 2: Diagnostic and therapeutic approaches for the biliary tree and gallbladder as erlotinib (OSI-774, Tarceva) have been evaluated in biliary cancers [71]. In a phase II study that included biliary cancer or hepatocellular cancer (although patients were not selected on the basis of EGFR expression), erlotinib was given contin- uously at a dose of 150 mg/day orally. Of the 36 evaluable pa- tients with biliary tumors, two had a partial response and seven (25%) were progression-free at 6 months. Conclusions Currently available medical approaches to the treatment of biliary malignancy are primarily palliative in intent. Chemotherapy appears to have a palliative benefit compared with the best supportive care in advanced gallbladder and bile duct cancers. When used as a radiosensitizer, 5- fluorouracil may also give palliative benefit for locally ad- vanced neoplasia. The role of chemotherapy in the adjuvant setting after surgical resection remains to be defined. Never- t heles s, we h ave t y pic a l ly c omb i ned adjuva nt c hemot her apy with radiation in patients with positive margins or regional lymph node involvement. For patients with locally advanced disease who would be surgical candidates if they attained tumor regression, we use systemic chemotherapy as part of a neoadjuvant multimodality approach. As immune, gene, an- tiangiogenic, and apoptotic strategies undergo further devel- opment, they will likely be applied to biliary cancers. Questions 1. Gallbladder cancer is more likely than hilar cholangiocarcinoma to recur with distant disease. a. true b. false 2. Gemcitabine-containing chemotherapy regimens have among the highest response rates in gallbladder cancer. a. true b. false 3. There is a trend for better survival in patients with unresectable biliary malignancies who receive systemic chemotherapy compared with best supportive care. a. true b. false c. may be true, but did not reach statistical significance 4. Pathways that may be involved in biliary malignancies include: ErbB-2, hepatocyte growth factor/Met, interleukin-6/ glycoprotein130, cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), transforming growth factor- beta (TGF-β), MUC1 and MUC4, beta-catenin, telomerase, and Fas/FasL. a. true b. false References 1. McMasters KM, Tuttle TM, Leach SD, et al. Neoadjuvant chemo- radiation for extrahepatic cholangiocarcinoma. Am J Surg 1997;174:605–8; discussion 608–9. 2. Heimbach JK, Haddock MG, Alberts SR, et al. Transplantation for hilar cholangiocarcinoma. Liver Transpl 2004;10(Suppl. 2): S65–8. 3. Mambrini A, Fiorentini G, Pennucci C, et al. Intra-arterial he- patic chemotherapy combined with systemic infusion of 5-FU in patients with advanced biliary tract cancers. Proc Am Soc Clin Oncol 2004;22:4197. 4. Jarnagin WR, Ruo L, Little SA, et al. 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SECTION 3 Specific conditions Diseases of the Gallbladder and Bile Ducts: Diagnosis and Treatment, Second Edition Edited By Pierre-Alain Clavien, John Baillie Copyright © 2006 by Blackwell Publishing Ltd SECTION 3.1 The gallbladder Diseases of the Gallbladder and Bile Ducts: Diagnosis and Treatment, Second Edition Edited By Pierre-Alain Clavien, John Baillie Copyright © 2006 by Blackwell Publishing Ltd CHAPTER 12 Natural history and pathogenesis of gallstones Beat Müllhaupt 12 OBJECTIVES • Understand the pathogenesis of gallstone formation • List the different risk factors of gallstone formation • Understand the natural history of asymptomatic and symptomatic gallstones • Describe the current medical treatment options for patients with symptomatic gallstone disease Introduction Gallstones are highly prevalent in industrialized countries, affecting 10 to 15% of men and up to 25% of women [1]. Al- though the majority of individuals with gallstones remain asymptomatic, symptomatic gallstone disease is considered the most common and costly digestive disease in the United States [2]. Studies in the 1960s reported cholecystectomy rates of 500,000 per year for the United States [3]; with the development of laparoscopic cholecystectomy in the late 1980s, this fi gure has risen further to an estimated 700,000 operations per year [4]. Over the past several decades, there have been major advances in our understanding of gallstone pathogenesis; with the improvements in, and wide availabil- ity of, imaging modalities such as ultrasound and computed tomography, the epidemiology and natural history of chole- lithiasis has been studied extensively. In this chapter, we discuss these developments, with special emphasis on their implications for the treatment of gallstone disease. Types of gallstones Gallstones are characterized by their chemical composition. They are classifi ed, somewhat arbitrarily, into cholesterol stones (>50% cholesterol content), mixed stones (20 to 50% cholesterol content), and pigment stones (<20% cholesterol content), the latter being composed primarily of calcium bili- rubinate. Early epidemiologic studies have suggested that 80 to 90% of all stones in Western countries were of the choles- terol or mixed type and only 10 to 20% were pigment stones 219 [5], but others have found pigment stones in up to 30% of individuals with cholelithiasis. In Asia, up to 70% of all gallstones are pigment stones. Due to the predominance of cholesterol gallstones in the United States, much of the research effort has focused on this type of stone and less is known about the pathogenesis of pigment stones. Pathogenesis of gallstone formation Components of normal bile The main components of bile are water, electrolytes, and or- ganic solutes, the latter consisting predominantly of bile salts, cholesterol, and phospholipids [6]. Bile salts are classified as either primary or secondary. The primary bile acids, cholic and chenodeoxycholic acid, are synthesized in the liver from cholesterol and then conjugated with either glycine or tau- rine. After excretion with bile fl uid into the duodenum, most of the bile acid pool is reabsorbed in the distal small bowel and recirculated via the enterohepatic circulation. A small amount (less than 5%) of bile salts enters the colon, where it undergoes deconjugation by bacteria, resulting in the formation of secondary bile acids (deoxycholic and litho- cholic acid) [7]. Most of the cholesterol found in bile is synthesized de novo in the liver. Cholesterol is insoluble in water and is therefore dependent on some other vehicle for its solubilization in bile. Understanding the mechanisms responsible for the solubili- zation of cholesterol has facilitated analysis of the biochemi- cal events occurring during the formation of cholesterol stones [8,9]. Diseases of the Gallbladder and Bile Ducts: Diagnosis and Treatment, Second Edition Edited By Pierre-Alain Clavien, John Baillie Copyright © 2006 by Blackwell Publishing Ltd 220 Section 3: Specific conditions Pathogenesis of cholesterol stones The formation of cholesterol gallstones has been separated into three stages: (1) cholesterol solubilization and satura- tion, (2) nucleation, and (3) stone growth [8]. Cholesterol is virtually insoluble in bile and therefore re- quires interaction with other molecules to be solubilized [8]. For many years, it was thought that cholesterol was main- tained in solution almost entirely by the formation of so- called micelles, composed of bile acids, phospholipids, and cholesterol. Bile acids are amphipathic compounds, contain- ing both hydrophilic and hydrophobic groups. When the bile acid concentration reaches a certain level (termed critical mi- cellar level), individual bile acid molecules aggregate into small clusters with their polar ends oriented outwardly and the hydrophobic portions oriented towards the inside of the cluster. Phospholipids enter this aggregate, leading to swell- ing of the micelle which in turn facilitates incorporation of cholesterol. Cholesterol molecules are ultimately transport- ed within the matrix of this structure. The concentration of bile acids and phospholipids relative to cholesterol has been thought to be the critical factor in determining cholesterol solubilization, and the relationship between these three sub- stances has commonly been depicted in form of a “cholesterol triangle” [9] (see also Chapter 1, Fig. 1.9) (Fig. 12.1). The concept of mixed micelle formation and its role in for- mation of cholesterol gallstones has recently been challenged by the demonstration that much of the biliary cholesterol exists in a somewhat different structure, termed a vesicle [9]. Vesicles are made up of phospholipid bilayers, similar to cell membranes, with interspersed bile acids [10]. Cholesterol is solubilized within the hydrophobic portion of the bilayer. The relative importance of micelles and vesicles in cholest- erol stone formation remains the subject of intensive research. The process by which cholesterol monohydrate crystals form and aggregate has been termed nucleation. The obser- vation that many normal individuals without gallstones secrete cholesterol-supersaturated bile suggests that factors other than the hepatic secretion of cholesterol-saturated bile are important for the formation of gallstones [11]. It has been shown that nucleation occurs more rapidly in the gallbladder bile of patients with cholesterol gallstones than in individu- als with saturated bile without stones [12]. This finding initi- ated efforts to identify the nature of either pronucleating or antinucleating factors. A heat-labile glycoprotein has been identifi ed in patients with cholesterol gallstones and has been shown to reduce nucleation time signifi cantly [13]. Increased gallbladder mucus secretion has also been reported to be a potent pronucleating factor [14]. Mucin secretion is stimu- lated by prostaglandins. Aspirin, an inhibitor of prostaglan- din synthesis, both significantly inhibits mucus secretion and reduces the incidence of experimentally induced choles- terol gallstones in an animal model [15]. This finding gener- ated considerable enthusiasm as it appeared feasible to prevent gallstone formation through prophylactic usage of Figure 12.1 Phase-equilibrium diagram of a model bile system consisting of sodium taurocholate, egg yolk lecithin, cholesterol, and water (10 g/dL total lipid concentration, 0.15 mol/L NaCl, pH 7.0, 37°C). Adapted from Donovan and Carey [9]. Chapter 12: Natural history and pathogenesis of gallstones 221 prostaglandin inhibitors. However, studies in humans have not found an effect of aspirin usage on gallstone formation [16] and this concept has been abandoned. Recently, a bacte- rial lipopolysaccharide has been shown to induce mucin hypersecretion suggesting that — contrary to the commonly accepted assumption — bacteria may play a role not only in the development of pigment gallstones but also in cholesterol stone formation [17]. In summary, although cholesterol supersaturation is commonly viewed as a prerequisite for cholesterol gallstone formation, the impact of pronucleating factors in vivo re- mains incompletely understood [18]. Efforts continue to un- derstand the role of cholesterol supersaturation and the balance between pronucleating and antinucleating factors in the formation of cholesterol stones. The role of the gallbladder Gallbladder contraction is induced by meals and mediated by the hormone cholecystokinin. When the gallbladder con- tracts, 70 to 80% of the fasting volume is released into the duodenum. Stasis of bile within the gallbladder has been im- plicated in the increased frequency of gallstone formation in patients after truncal vagotomy and during pregnancy [19]. Radioisotope and manometric studies have confirmed that gallbladder stasis and decreased gallbladder emptying occur during the early stages of formation of experimentally in- duced cholesterol gallstones [20]. High progesterone levels have also been shown to reduce gallbladder contractility in an animal model [21], a mechanism that may contribute to the increased risk for gallstone formation during pregnancy. Further evidence implicating gallbladder stasis as an etiol- ogic factor in cholesterol gallstone formation comes from bil- iary scintigraphic studies of human patients with gallstones, in whom a decreased motor response to cholecystokinin stimulation has been noted. Decreased gallbladder emptying has been demonstrated in patients with cholesterol gallstones [22] as well as, in the absence of stones, in individuals with biliary cholesterol crystals. The mechanism by which stasis of bile within the gallblad- der promotes cholesterol gallstone formation remains poorly defined. Conceivably, stone growth from cholesterol crystals is a slow process. Even with enough time for microcrystals to nucleate, in subjects with normal gallbladder function these small cholesterol aggregates are likely to be ejected into the duodenum before growing into macroscopic gallstones. Fur- thermore, gallbladder stasis may be associated with altera- tions in gallbladder absorptive or secretory function or with sequestration of bile acids in the gallbladder, reducing the amount of bile salts available for cholesterol solubilization [23]. Pathogenesis of pigment stones Pigment stones are characterized by their low cholesterol content and their high concentration of bilirubin, which is usually in excess of 40%. Bilirubin is secreted by the liver into the bile mostly in its diglucuronide form with only small amounts of the monoglucuronide and unconjugated forms. As for cholesterol, bile salts facilitate solubilization of the monoglucuronide and unconjugated forms of bilirubin. The unconjugated form is hydrophobic and may precipitate from solution as calcium salts or bilirubin polymers [24]. It is believed that pigment stones occur when the bile is super- saturated with unconjugated bilirubin. Pigment stones are associated with diverse clinical conditions and can be conve- niently divided into “black stones” and “brown stones.” Black pigment stones occur in patients with chronic hemo- lysis, liver cirrhosis, or compromised ileal function, as with Crohn’s disease or ileal resection. In patients with hemolysis, secretion of bilirubin into bile may be increased more than 10-fold, with a shift from diconjugates to monoconjugates. Bilirubin monoconjugates are more sensitive to hydrolysis by endogenous beta-glucuronidase, leading to accumulation of unconjugated bilirubin which subsequently precipitates with calcium. The pathogenesis of gallstone formation in pa- tients with cirrhosis is less well understood, but mild hemoly- sis and bile salt hyposecretion leading to reduced solubility of unconjugated bilirubin may play a role. Patients with Crohn’s disease and extensive ileitis have higher levels of bilirubin fl ux through the liver and higher biliary bilirubin concentra- tions. Results from animal experiments suggest that this may be due to bile salt malabsorption in the ileum resulting in h ig h amou nts of intracolon ic bile s alt s. This leads to solubi l i- zation of intracolonic unconjugated bilirubin, which is then free to be reabsorbed, transported back to the liver, and ex- creted into the bile, thereby leading to increased concentra- tion of biliary bilirubin [25]. Similar to cholesterol stone formation, a variety of other factors may contribute to pigment stone formation, including secretion by the gallbladder of mucous glycoproteins, biliary stasis, biliary calcium concentration, and bile acidifi cation [23]; the exact contribution of each of these factors remains to be elucidated. The role of bacterial infection in the patho- genesis of black pigment stones has long been discussed; there are some indications that bacteria may play a role, but find- i ngs h ave bee n i nco nclu s ive to d ate [26 ] . Brown pigment stones can be located throughout the intrahepatic and/or extrahepatic biliary tract and are the typical type of gallstone associated with bacterial infection and biliary stasis [27]. Bacterial enzymes hydrolyze biliary lipids, conjugated bilirubin, and bile salts. The resultant free bile acids, freefatty acids, and unconjugated bilirubin precip- itate as such or form insoluble calcium salts. Mucin glycopro- teins and bacterial debris may contribute to the growing gallstone. Common duct stones Gallstones located in parts of the biliary tree other than the gallbladder may be classifi ed as either primary, those that are 222 Section 3: Specific conditions formed in the bile duct, or secondary, those that are formed in the gallbladder and passed through the cystic duct into the common duct or the intrahepatic bile ducts. Epidemiologic evidence suggests that most common duct stones arise in the gallbladder [28]. Most patients with cholesterol stones in the common duct also have gallbladder stones of identical com- position. In contrast, patients with pigment stones in the common duct often do not have corresponding stones in the gallbladder. Pigment stones, particularly those of the brown pigment type, are therefore thought to form anywhere in the biliary tree, very often in the intrahepatic portion of the bili- ary tree; they probably constitute the majority of primary common duct stones. Although the main factors contribut- ing to the formation of primary common duct stones appear to be biliary bacterial infections and stasis of bile in the com- mon duct, abnormal sphincter of Oddi activity has also been discussed as a contributing factor. Wong and colleagues re- ported elevated common bile duct pressures at operation in patients with common duct stones [29]. However, two other groups could not confirm this finding [30,31]. Whether the increased prevalence of gallstones in patients with juxtapap- illary duodenal diverticula is due to a motor abnormality of the sphincter of Oddi has also been controversial. It has been suggested that sphincter insufficiency causes higher rates of bacterial contamination of the biliary tree which in turn leads to higher frequencies of brown pigment stone forma- tion [32]. Additional studies are needed to clarify the role of motor abnormalities of the sphincter of Oddi in the patho- genesis of primary common duct stones. In the Far East and Japan, intrahepatic stones or hepatico- lithiasis are very prevalent, whereas in the West they are extremely rare [33]. Most intrahepatic stones are also brown pigment stones (calcium bilirubinate stones) where bacterial infection and bile stasis are also thought to be of pathogenetic importance (see above). However, intrahepatic brown pig- ment stones include more cholesterol and less calcium biliru- binate and bile acid compared to brown pigment stones in the extrahepatic bile ducts [34]. In addition, recently an in- creased number of primary cholesterol stones in the intrahe- patic bile ducts have also been identified [35]. The formation of cholesterol-rich brown pigment stones and cholesterol stones in the intrahepatic bile ducts suggests the possibility that there might be an underlying metabolic defect. There is recent evidence that the formation of these stones may be due to decreased secretion of phospholipids as a consequence of such a metabolic defect leading to the formation of intrahe- patic stones [36]. Biliary sludge Biliary sludge was first described with the advances of ab- dominal ultrasonography as an echogenic material in the gallbladder that shifts slowly with positioning of the patient [37] (Fig. 12.2). Similar pathogenetic mechanisms as in gall- stone disease are assumed to apply to the formation of biliary sludge, and the role of biliary sludge as a precursor of choles- terol and pigment gallstones has been proposed by Lee and colleagues [38]. Gallbladder sludge, as determined ultraso- nographically, has been presumed to be a manifestation of biliary stasis. It has been demonstrated that sludge is com- posed, in part, of calcium bilirubinate crystals, cholesterol monohydrate crystals, and gallbladder mucus [39]. In a study of patients receiving total parenteral nutrition (TPN), sludge could be detected in all patients after 6 weeks of TPN [40]. With continuation of TPN, stones developed in almost half of Figure 12.2 Transabdominal ultrasound of a gallbladder containing large amounts of sludge and multiple gallstones generating characteristic acoustic shadowing. Chapter 12: Natural history and pathogenesis of gallstones 223 these patients during follow-up. On the other hand, the rein- stitution of oral feedings led to disappearance of sludge within 4 weeks. Risk factors for gallstone formation A large number of diverse factors predispose individuals to the development of gallstones (Table 12.1). The prevalence of gallstones varies greatly among different ethnic groups sug- gesting that genetic factors may play an important role. Gall- stone prevalence in certain Asian countries is 3 to 5%, but populations in Europe and North America have an overall prevalence of 10 to 20%; in certain ethnic subgroups such as the North American Pima Indians and Chippewa, gallstones rates reach 60%. In a recent study from Mexico, it was shown that the development of gallstones in the Mexican popula- tion was associated with characteristics of the Amerindian population [41]. Further evidence in favor of genetic influ- ence for the development of symptomatic gallstone disease was provided by a Swedish study of over 43,000 twin pairs [42]. In their study, they found that heritability was the major susceptibility factor for symptomatic gallstones. There is also considerable temporal variation in gallstone prevalence, sup- porting an influence of dietary factors and lifestyle. It has been argued that the ancient Greeks knew renal colic but did not know gallstone disease, and this has been attributed to their diet and style of living. Several studies in more recent times have also shown increases in the prevalence of gall- stones over time. Gallstones are twice as common in women as in men, and the prevalence increases with age. The family history also seems to be of importance: first-degree relatives of gallstone patients have a 4.5-fold risk of having gallstones compared to matched controls [43]. Obesity has long been identified as an important risk factor. One study reported a six-fold increased risk for gallstone formation in very obese women compared to lean women [44]. Whether hypertriglyceridemia repre- sents an additional independent risk factor remains contro- versial. Rapid weight loss, either due to dietary measures or bariatric surgery, is associated with a high incidence of gallstones [45]. There is some evidence that this risk can be reduced by the administration of ursodeocycholic acid [46]. A peculiar form of cholelithiasis was recently described by Rosmorduc [47]. All patients described in this study shared the following features: at least one episode of biliary colic, pancreatitis, or cholangitis; biochemical evidence of chronic cholestatis; recurrence of symptoms after cholecystectomy; presence of echogenic material in the intrahepatic bile ducts; and prevention of recurrence by ursodeoxycholic acid thera- py. In all these patients a mutation in the ABCB4 gene could be identified. The ABCB4 gene, formerly called MDR3 gene is the phosphatidylcholine translocator across the canalicular membrane of the hepatocyte. Accordingly, the phospholip- ids concentration is low leading to a high cholesterol/ phospholid ratio and cholesterol crystals in the bile of these patients. Therefore, this clinical syndrome is referred to as low phospholipids-associated cholelithiasis. In a second study, mutations in the ABCB4gene were found in 56% of pa- tients presenting the symptoms mentioned above and three independent clinical features were strongly associated with ABCB4 mutations: recurrence of symptoms after cholecys- tectomy; intrahepatic hyperechoic foci; intrahepatic sludge or microlithiasis and age less than 40 years at the onset of symptoms [48]. Therefore ABCB4 gene mutations might represent a major genetic risk factor for a symptomatic and recurring form of cholelithiasis occurring in young adults. Pregnancy predisposes women to gallstones, probably due to a combination of the effects of estrogens causing an in- crease in biliary cholesterol saturation and progesterones causing atony of the gallbladder. In a study by Coelho and colleagues performed in Brazil, 4% of nulliparous women had gallstones compared to 35% of women with six or more pregnancies [49]. As mentioned above, biliary sludge com- monly develops during pregnancy and may evolve into gallstones or may resolve after the birth [50]. Patients with Down syndrome have an increased preva- lence of gallstones and, in a recent study, it was demonstrated that adults with Down syndrome also have a higher risk for symptomatic gallstone disease [51]. Table 12.1 Risk factors for gallstone formation. Cholesterol gallstones American Indians > Hispanics > Whites > Blacks Western countries Family history Female gender Pregnancy, multiparous Estrogen supplementation Obesity Age Weight loss Fasting, total parenteral nutrition Drugs (octreotide, ceftriaxone, clofibrate) Noninsulin-dependent diabetes mellitus ABCB4 gene mutations Black pigment gallstones Chronic hemolysis Cirrhosis Alcoholism Ileal disease Age Brown pigment stones Rural Asia Biliary tract infection Juxtapapillary diverticula [...]... between the duodenal bulb (DB) and the gallbladder (GB) (B) The biliary tree is visible as a result of the retrograde flow of contrast material from the duodenal bulb into the gallbladder and cystic duct (larger arrowhead) and then into the intrahepatic ducts (arrow) and common bile duct (CBD) The semilunar lucencies within the gallbladder are gallstones (small arrowhead) (Reprinted by permission of the. .. Consecutive distention of the gallbladder induces the release of mediators, such as prostaglandin E2 and I 2, which cause an inflammatory response within the gallbladder [5] Infection of the accumulated bile fluid is secondary (Fig 13.1) Positive bile cultures are found in 40 to 60 % of patients and include common enteric organisms These are Gram-positive and Gram-negative aerobes and anaerobes: Escherichia... management of acute cholecystitis consists of fasting, intravenous fluids, analgesia, and antibiotics It is postulated that under this treatment the gallstone disimpacts and falls back into the gallbladder, which allows emptying of the gallbladder, resulting in reduction of the inflammation The theoretical aim of fasting is to rest the gallbladder, to reduce bile secretion, and therefore to decrease gallbladder. .. attacks of mild acute cholecystitis, caused by transient obstruction of the cystic duct by stones, lead to the development of a chronic inflammation of the wall of the gallbladder Besides the reparative inflammatory changes, the repetitive mucosal trauma produced by the gallstones could play a pathogenetic role as well Because of the poor correlation between the severity of the inflammation and the number and. .. dissolution of gallstones by methyl-tert-butyl ether Lancet 1988;2: 2 76 7 Diseases of the Gallbladder and Bile Ducts: Diagnosis and Treatment, Second Edition Edited By Pierre-Alain Clavien, John Baillie Copyright © 20 06 by Blackwell Publishing Ltd 13 C H A P T E R 13 Acute and chronic cholecystitis Stefan Breitenstein, Armin Kraus and Pierre-Alain Clavien OBJECTIVES • Describe the pathogenesis of acute and. .. gallstones was in the 5th century by the Greek physician Trallianus, who wrote of calculi within the bile ducts The first known successful cholecystolithotomy was performed by Dr Joenisius in 167 6, when he noted an abdominal wall abscess that had ruptured, with the discharge of pus and bile The 19th century brought the development of anesthesia and more detailed knowledge of biliary colic and intermittent... of “cooling down” the inflammation and to perform elective open cholecystectomy several weeks later At the end of the 1970s, the concept changed to “early” open cholecystectomy, meaning within the first 36 to 72 hours from the onset of symptoms With the introduction of laparoscopic cholecystectomy at the beginning of the 1990s the question of timing arose again At the beginning of the decade, acute cholecystitis... technetium-labeled iminodiacetic acid derivative (99 m technetium iminodiacetic analogue) is injected intravenously and will normally be taken up by the liver and then the gallbladder Uptake by the liver and excretion into the duodenum without filling of the gallbladder is indicative for occlusion of the cystic duct This test has a sensitivity of up to 86% in the correct clinical setting [ 16] Although... Treatment of an uncomplicated choledochoduodenal fistula is usually not indicated [11,13,14] Most authors agree that the therapy is dictated by the symptoms of the underlying peptic ulcer and not by the presence of the fistula alone [11,15, 16] Closure of the fistula may be achieved by conservative management of the ulcer disease Surgical treatment of the fistula may be necessary in the presence of severe... different from the mortality rate in the two-stage group 16 patients underwent secondary repair of the fistula; no death occurred among these patients 2 46 Section 3: Specific conditions described but is often difficult as extensive adhesions occur in the area of the gallbladder [74] A two-stage operation is therefore usually advised Laparoscopy may be useful to establish the diagnosis and offers a minimally . for the solubili- zation of cholesterol has facilitated analysis of the biochemi- cal events occurring during the formation of cholesterol stones [8,9]. Diseases of the Gallbladder and Bile Ducts: . the gallbladder, resulting in reduction of the infl ammation. The theoretical aim of fasting is to rest the gallbladder, to re- duce bile secretion, and therefore to decrease gallbladder dis- tention. to the mucosa and mucosal edema leads to lymphatic and venous obstruction, and possibly lo- calized areas of ischemia. Bile salts become concentrated in Diseases of the Gallbladder and Bile Ducts: